Minimal Residual Disease (MRD) Data in Hematologic Malignancy Drug Applications and Prescribing Information: FDA Analysis

Introduction: In the past decade, multiple studies have reported the prognostic and predictive value of MRD status in specific hematologic malignancies (HM). Because clinical trials are increasingly incorporating MRD status as a biomarker and efficacy endpoint, the adequacy of the MRD data to inform the prescribing information (PI) is relevant for the design and conduct of pivotal clinical trials. We present an analysis of the trends in inclusion of MRD data in pivotal trials in HMs and regulatory decisions made by the U.S. Food and Drug Administration (FDA). Methods: We reviewed FDA internal databases for original and supplemental new drug applications (NDAs) and biologics licensing applications (BLAs) submitted 1/2014-12/2020 to support approval of therapies (drugs, biologics, and cellular therapies) for HM. MRD data were evaluated for two time periods to inform potential trends: 1/2014-6/2017 (period 1) and 7/2017-12/2020 (period 2). Clinical study reports, selected datasets, FDA clinical reviews, and the proposed and approved PIs were examined for inclusion of MRD data, and FDA assessments of the adequacy of the MRD data for inclusion in the PI were reviewed. Results: Of 196 NDAs or BLAs involving HM submitted between 2014-2021, 53 (27%) had MRD data, including 53 pivotal trials. The trials included patients with chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, and multiple myeloma. Twenty-one applications and pivotal trials with MRD data were submitted in period 1, and 32 applications and 35 trials were submitted in period 2. Three trials were resubmitted in period 2. MRD evaluation was specified as a secondary and exploratory endpoint in 35 (66%) and 19 (36%) of the trials, respectively. Of the 53 trials, MRD data was proposed by the Applicant for inclusion in the PI in 41 (77%) but was ultimately included in 25 (47%). Of the trials for which MRD data was proposed in labeling, MRD data were deemed adequate by FDA in 81% of studies in period 1 (13/16) and 48% of studies in period 2 (12/25). MRD assays in the PI included polymerase chain reaction, flow cytometry, and next-generation sequencing in 18 (72%), 5 (20%) and 4 (16%) of the trials, respectively, with the clinical threshold for test positivity ranging from 10 -3 to 10 -5. For 11 trials with MRD data in the PI (44%), the MRD was evaluated regardless of clinical response, and in 14 trials (56%) MRD was evaluated in patients achieving a specific clinical response. The leading reasons for excluding MRD data from the PI were analytical and test validation deficiencies (e.g., incomplete test characteristics data, lack of test validation overall or in that disease) followed by performance issues (e.g., high amount of test failure, inability to identify a clone) and issues with trial conduct or design (e.g., inadequate data collection, statistical issues). Conclusion: A quarter of HM drug applications, including 53 pivotal trials, submitted to the FDA between 2014-2020 included MRD data. Characterization of regulatory actions showed that despite the increasing number of submissions proposing MRD data for inclusion in the PI, rates of inclusion of MRD data in the PI did not reflect this increase. Improvements in assay validation and performance characteristics, robust collection of MRD data, and appropriate statistical planning can enable greater representation of MRD data in prescription drug labeling. Disclosures No relevant conflicts of interest to declare.

Patient access to biological medications for ulcerative colitis

This article considers the evidence for using different biologics in ulcerative colitis (UC), in particular the landmark head-to-head VARSITY trial. It reviews and addresses questions about VARSITY and its study design, including potential underdosing of adalimumab and lack of steroid tapering. It weighs up the implications of the evidence for clinical practice, as well as how this evidence supports increasing patient access to vedolizumab. It also assesses how the COVID-19 pandemic has changed the prescribing of biologics in ulcerative colitis, with a focus on subcutaneous adalimumab as the most commonly prescribed first biologic in UC. Declaration of interest This article was commissioned and funded by Takeda UK Ltd, who suggested the author and topic. Takeda UK Ltd also reviewed and approved the content. Prescribing information for vedolizumab (Entyvio) can be found at the end of the article.

Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality

<b><i>Background:</i></b> Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. <b><i>Summary:</i></b> Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to &#x3c;5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels &#x3c;5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. <b><i>Key Messages:</i></b> Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.